West Nile virus (WNV) is a mosquito-borne positive strand RNA virus from genus Flaviviruses in the family Flaviviridae. Until late nineties WNV caused only sporadic outbreaks of relatively mild infections in Africa, Europe and Australia. However, the emergence in 1999 and rapid spread of highly pathogenic strain of WNV in Americas and outbreaks in Europe resulted in dramatic burst of research on this virus which significantly advanced our understanding of how this virus replicates and causes fatal disease. My laboratory has been focusing on molecular aspects of WNV replication and its interactions with the vector and the host. Using infectious clones of attenuated and virulent strains of WNV we have began to unravel viral determinants of virulence and using knockout cells and mice we have began to identify host factors controlling virus replication. More recently we have focused on viral and host non-coding RNAs and have shown that they play important roles in WNV replication and virus-host interactions. We have identified a cellular mechanism for generation of WNV non-coding subgenomic RNA (sfRNA) and have shown that sfRNA has multiple functions in modulating host response to infection. We have also discovered that WNV produce virally-encoded microRNA that plays essential role in WNV replication in mosquito vector and that mosquito cells down regulate expression of one of its own microRNAs in response to WNV infection in order to control virus replication. Further deciphering of the complex and interconnected networks of interactions between viral and host non-coding RNAs as well as viral and host proteins will result in greater understanding of WNV-host interactions and help in developing effective anti-viral treatments.